GI Adenocarcinoma
Conditions
Keywords
Amgen, Phase 1, Clinical Trial, Oncology, GI adenocarcinoma, Immunotherapy
Brief summary
The purpose of this Phase 1 study is to determine if AMG 211 given as a continous intravenous (IV) infusion is safe and tolerable in adult participants that have advanced gastrointestinal adenocarcinoma. The study will be conducted in multiple sites and test increasing doses of AMG 211. The safety of participants will be monitored by intensive assessment of vital signs, electrocardiograms, physical examinations, and laboratory tests. Efficacy will be assessed by the usual imaging procedures and their interpretation.
Interventions
DRUGAMG 211
continuous intravenous infusion (cIV) infusion in cycles from 7 to 28 days
Sponsors
MedImmune LLC
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Informed consent provided * 18 years or older * Advanced relapsed/refracted gastrointestinal adenocarcinoma * At least 1 measurable tumor lesion * Tumor tissue available or is willing to undergo biopsy of a tumor lesion before the start of treatment * Adequate hematological, renal, and liver function * Body weight ≥ 45 kg * Other inclusion criteria may apply
Exclusion criteria
* Malignancy other than gastrointestinal (GI) adenocarcinoma requiring current therapy * Evidence of uncontrolled systemic disease, active infection, Hepatitis B and/or C, human immunodeficiency virus (HIV), history of cardiac disease, history of significant central nervous system (CNS) disease, history of chronic autoimmune disease (with the exception of stable type 1 diabetes) * Major surgery within 28 days of study day 1 * Currently receiving treatment in another investigational device or drug study, or less than 28 days since ending treatment in another investigational device or drug study. Other investigational procedures while participating in this study are excluded. Exception to this criterion is the participation in the optional Imaging Study and all procedures related to this study. * Treatment with any chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal therapy for cancer within 14 days prior to study entry and not recovered from treatment * Unresolved toxicities from prior anti-tumor therapy * Males or Females of reproductive potential, and unwilling to practice an acceptable method of effective birth control while on study through 30 days after receiving the last dose of study drug * Females who are pregnant, planning to become pregnant, lactating/breastfeeding or who plan to breastfeed while on study through 30 days after receiving the last dose of study drug * Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicities (DLTs) | 28 days | A DLT was defined as any of the following occurring during the first 28 days of treatment and regarded by the investigator and/or sponsor as related to AMG 211. Hematological DLTs: absolute neutrophil count (ANC) \< 0.5 × 10⁹ cells/L for ≥ 7 days; febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection) with ANC \< 0.5 × 10⁹ cells/L and fever ≥ 38.5°C; platelets \< 25 × 10⁹ cells/L ≥ 7 days. Non-hematological DLTs: any AMG 211-related ≥ grade 3 non-hematological toxicity, excluding nausea and vomiting not refractory to anti-emetics, flare-up of pain due to potential increase in tumor volume, cytokine release syndrome manageable with symptomatic treatment and/or infusion interruption of up to 2 days. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was used to assess toxicities/adverse events. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From first dose of study drug through end of treatment + 30 days (median time frame was 75.5 days). | An adverse event (AE) was defined as any untoward medical occurrence, which does not necessarily have a causal relationship with study treatment. A serious adverse event (SAE) was defined as an event that: was fatal or life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/borth defect; or other significant medical event. A TEAE was defined as any AE starting on or after the first dose of study drug and up to and including 30 days after the end of last dose of study drug. The severity of each adverse event was graded using CTCAE version 4.03 criteria (1=mild, 2=moderate, 3=severe, 4=life-threatining, 5=death). 'Any TEAE' includes both serious and non-serious TEAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Area under the serum concentration-time curve (AUC) from time 0 to the last quantifiable concentration was estimated using the linear trapezoidal method. |
| Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 28 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Area under the serum concentration-time curve (AUC) from time 0 to the last quantifiable concentration was estimated using the linear trapezoidal method. |
| Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Area under the serum concentration-time curve from time 0 to infinity was estimated using the linear trapezoidal method |
| Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 28 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Area under the serum concentration-time curve from time 0 to infinity was estimated using the linear trapezoidal method |
| Terminal Half-life (T1/2) of AMG-211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Terminal half-life (t1/2,z) calculated as t1/2,z = ln(2)/λz, where λz was the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase. |
| Terminal Half-life of AMG-211 in Cycle 1 in Participants Who Received Dosing for 28 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Terminal half-life (t1/2,z) calculated as t1/2,z = ln(2)/λz, where λz was the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase. |
| Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion | Css was calculated as the average concentration between achievement of plateau and the end of infusion. |
| Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 28 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Css was calculated as the average concentration between achievement of plateau and the end of infusion. |
| Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Serum clearance (CL) calculated as CL = (actual dose)/(serum concentrations at steady-state \[Css\] x 24). |
| Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Levels of AMG 211 in plasma samples collected during this study were analyzed using an electrochemiluminiscence assay. The lower limit of quantification (LLOQ) of the assay was 0.10 ng/mL. |
| Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Volume of distribution at steady-state calculated as (CL x t1/2,z)/0.693. |
| Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 28 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Volume of distribution at steady-state calculated as (CL x t1/2,z)/0.693. |
| Number of Participants With Anti-AMG 211 Antibody Formation | Predose and 24 hours after the end of infusion during each treatment cycle, until 4 weeks after the last dose. Median time frame was 75.5 days. | Blood samples collected during the study were tested for anti-AMG 211 binding antibodies using an electrochemiluminescence-based bridging immunoassay. The number of participants with anti-AMG 211 antibody formation includes participants with a negative or no result at baseline and a positive antibody binding result postbaseline. |
| Number of Participants With an Overall Objective Response | Disease response was assessed every second cycle (8-10 weeks) until 4 weeks after the last dose. The median time frame was 75.5 days. | Disease response was assessed by radiological imaging using standardized contrast-enhanced magnetic imaging (MRI) or computed tomography (CT), and evaluated according to the modified Immune-Related Response Criteria (irRC). Overall objective response was defined as a best response of immune-related Complete Response (irCR) or immune-related Partial Response (irPR), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment. irCR: Complete disappearance of all lesions and no new lesions. irPR: Decrease in tumor burden ≥ 50% relative to baseline. |
| Duration of Response | Disease response was assessed every second cycle (8-10 weeks) until 4 weeks after the last dose. The median time frame was 75.5 days. | Duration of response was defined as the number of days between the date of the first tumor assessment indicating an objective response through to the subsequent date of progression as classified by modified irRC or death due to any cause. Analyzed in participants with an overall objective response. Overall objective response was defined as a best response of immune-related Complete Response (irCR) or immune-related Partial Response (irPR), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment. irCR: Complete disappearance of all lesions and no new lesions. irPR: Decrease in tumor burden ≥ 50% relative to baseline. |
| Time to Response | Disease response was assessed every second cycle (8-10 weeks) until 4 weeks after the last dose. The median time frame was 75.5 days. | Time to response was defined as the number of days from the first administration of AMG 211 to the first objective assessment of response as per modified irRC. Analyzed in participants with an overall objective response. Overall objective response was defined as a best response of immune-related Complete Response (irCR) or immune-related Partial Response (irPR), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment. irCR: Complete disappearance of all lesions and no new lesions. irPR: Decrease in tumor burden ≥ 50% relative to baseline. |
| Time to Tumor Progression in Participants Treated at the Maximum Tolerated Dose (MTD) | From first dose of AMG 211 until tumor progression, assessed through the end of study (up to 4 weeks after the last dose). The median time frame was 75.5 days. | Disease was assessed by radiological imaging using standardized contrast-enhanced MRI or CT, and evaluated according to the modified irRC. Immune-related progressed disease (irPD) was defined as an increase in tumor burden ≥ 25% relative to nadir (minimum recorded tumor burden), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment. |
| Progression Free Survival (PFS) at 6 Months in Participants Treated at the MTD | 6 months | PFS was defined as the percentage of participants who were progression-free at 6 months. Immune-related progressed disease (irPD) was defined as an increase in tumor burden ≥ 25% relative to nadir (minimum recorded tumor burden), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment. |
| Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | Serum clearance (CL) calculated as CL = (actual dose)/(serum concentrations at steady-state \[Css\] x 24). |
| Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days | Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion. | — |
Countries
Germany, Netherlands
Participant flow
Recruitment details
This study was conducted at 5 centers in the Netherlands and Germany. Participants were enrolled from 27 November 2014 to 28 March 2017.
Pre-assignment details
This study was to be conducted in 2 parts: dose-escalation and dose-expansion (planned to enroll additional participants to gain further clinical experience with AMG 211). The dose expansion part was not conducted (study terminated early). In the dose-escalation cohorts, participants were assigned sequentially into cohorts as they opened.
Participants by arm
| Arm | Count |
|---|---|
| AMG 211 200 µg/Day for 7/14 Days In cycle 1 participants received 200 µg/day AMG 211 administered as a cIV infusion at a constant flow rate for 7 days followed by a 3-week treatment-free interval. In cycle 2 and thereafter, participants received 200 µg/day AMG 211 administered as a cIV infusion for 14 days followed by a 2-week treatment-free interval. | 3 |
| AMG 211 200 µg/Day for 14 Days Participants received 200 µg/day AMG 211 administered as a cIV infusion for 14 days followed by a 2-week treatment-free interval. | 3 |
| AMG 211 400 µg/Day for 14 Days Participants received 400 µg/day AMG 211 administered as a cIV infusion for 14 days followed by a 2-week treatment-free interval. | 3 |
| AMG 211 800 µg/Day for 14 Days Participants received 800 µg/day AMG 211 administered as a cIV infusion for 14 days followed by a 2-week treatment-free interval. | 5 |
| AMG 211 1600 µg/Day for 14 Days Participants received 1600 µg/day AMG 211 administered as a cIV infusion for 14 days followed by a 2-week treatment-free interval. | 3 |
| AMG 211 1600 µg/Day for 28 Days Participants received 1600 µg/day AMG 211 administered as a cIV infusion for 28 days followed by a 2-week treatment-free interval. | 3 |
| AMG 211 3200 µg/Day for 14 Days Participants received 3200 µg/day AMG 211 administered as a cIV infusion for 14 days followed by a 2-week treatment-free interval. | 6 |
| AMG 211 3200 µg/Day for 28 Days Participants received 3200 µg/day AMG 211 administered as a cIV infusion for 28 days followed by a 2-week treatment-free interval. | 3 |
| AMG 211 6400 µg/Day for 14 Days Participants received 6400 µg/day AMG 211 administered as a cIV infusion for 14 days followed by a 2-week treatment-free interval. | 3 |
| AMG 211 6400 µg/Day for 28 Days Participants received 6400 µg/day AMG 211 administered as a cIV infusion for 28 days followed by a 2-week treatment-free interval. | 10 |
| AMG 211 12,800 µg/Day for 28 Days Participants received 12,800 µg/day AMG 211 administered as a cIV infusion for 28 days followed by a 2-week treatment-free interval. | 2 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 1 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Decision by sponsor | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | AMG 211 200 µg/Day for 7/14 Days | AMG 211 200 µg/Day for 14 Days | AMG 211 400 µg/Day for 14 Days | AMG 211 800 µg/Day for 14 Days | AMG 211 1600 µg/Day for 14 Days | AMG 211 1600 µg/Day for 28 Days | AMG 211 3200 µg/Day for 14 Days | AMG 211 3200 µg/Day for 28 Days | AMG 211 6400 µg/Day for 14 Days | AMG 211 6400 µg/Day for 28 Days | AMG 211 12,800 µg/Day for 28 Days | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 11.7 | 66.0 years STANDARD_DEVIATION 11.5 | 56.7 years STANDARD_DEVIATION 12 | 60.6 years STANDARD_DEVIATION 11.7 | 65.3 years STANDARD_DEVIATION 8.1 | 64.0 years STANDARD_DEVIATION 4.6 | 64.5 years STANDARD_DEVIATION 11.1 | 67.3 years STANDARD_DEVIATION 7.6 | 66.0 years STANDARD_DEVIATION 13.1 | 62.2 years STANDARD_DEVIATION 9.7 | 66.0 years STANDARD_DEVIATION 4.2 | 63.3 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 6 Participants | 3 Participants | 3 Participants | 10 Participants | 2 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race Black (or African American) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race White | 3 Participants | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 6 Participants | 3 Participants | 2 Participants | 9 Participants | 2 Participants | 42 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 1 Participants | 21 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants | 4 Participants | 1 Participants | 3 Participants | 3 Participants | 0 Participants | 2 Participants | 7 Participants | 1 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 1 / 3 | 0 / 5 | 1 / 3 | 1 / 3 | 1 / 6 | 0 / 3 | 0 / 3 | 1 / 10 | 2 / 2 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 5 / 5 | 3 / 3 | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 3 | 9 / 10 | 2 / 2 |
| serious Total, serious adverse events | 1 / 3 | 2 / 3 | 2 / 3 | 4 / 5 | 2 / 3 | 1 / 3 | 6 / 6 | 3 / 3 | 1 / 3 | 9 / 10 | 1 / 2 |
Outcome results
Primary
Number of Participants With Dose-Limiting Toxicities (DLTs)
A DLT was defined as any of the following occurring during the first 28 days of treatment and regarded by the investigator and/or sponsor as related to AMG 211. Hematological DLTs: absolute neutrophil count (ANC) \< 0.5 × 10⁹ cells/L for ≥ 7 days; febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection) with ANC \< 0.5 × 10⁹ cells/L and fever ≥ 38.5°C; platelets \< 25 × 10⁹ cells/L ≥ 7 days. Non-hematological DLTs: any AMG 211-related ≥ grade 3 non-hematological toxicity, excluding nausea and vomiting not refractory to anti-emetics, flare-up of pain due to potential increase in tumor volume, cytokine release syndrome manageable with symptomatic treatment and/or infusion interruption of up to 2 days. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was used to assess toxicities/adverse events.
Time frame: 28 days
Population: Safety Analysis Set: all participants who enrolled and received at least one dose of AMG 211. Participants were evaluable for a DLT if they received at least 90% of planned doses in the first treatment cycle.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence, which does not necessarily have a causal relationship with study treatment. A serious adverse event (SAE) was defined as an event that: was fatal or life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/borth defect; or other significant medical event. A TEAE was defined as any AE starting on or after the first dose of study drug and up to and including 30 days after the end of last dose of study drug. The severity of each adverse event was graded using CTCAE version 4.03 criteria (1=mild, 2=moderate, 3=severe, 4=life-threatining, 5=death). 'Any TEAE' includes both serious and non-serious TEAEs.
Time frame: From first dose of study drug through end of treatment + 30 days (median time frame was 75.5 days).
Population: Safety Analysis Set: all participants who enrolled and received at least one dose of AMG 211.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 4 TEAE | 0 Participants |
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAE | 1 Participants |
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 0 Participants |
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-threatening TEAE | 0 Participants |
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Non-STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAE | 3 Participants |
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 3 Participants |
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (STEAE) | 1 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 4 TEAE | 0 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (STEAE) | 2 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 3 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 0 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAE | 3 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-threatening TEAE | 0 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAE | 2 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Non-STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAE | 3 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 3 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAE | 2 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 4 TEAE | 1 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (STEAE) | 2 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Non-STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-threatening TEAE | 0 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 1 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 5 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAE | 4 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 0 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-threatening TEAE | 0 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of AMG 211 | 2 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 4 TEAE | 1 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Non-STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | STEAE leading to discontinuation of AMG 211 | 2 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAE | 5 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (STEAE) | 4 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Non-STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 4 TEAE | 1 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (STEAE) | 2 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAE | 1 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 3 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAE | 3 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-threatening TEAE | 0 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 1 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (STEAE) | 1 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 3 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-threatening TEAE | 0 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 4 TEAE | 1 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Non-STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAE | 2 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAE | 3 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 1 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAE | 4 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (STEAE) | 6 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-threatening TEAE | 1 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 4 TEAE | 1 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 6 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAE | 6 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 0 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Non-STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAE | 3 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAE | 3 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 4 TEAE | 1 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (STEAE) | 3 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of AMG 211 | 1 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 0 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | STEAE leading to discontinuation of AMG 211 | 1 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 3 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Non-STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-threatening TEAE | 0 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 4 TEAE | 0 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAE | 1 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Non-STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-threatening TEAE | 0 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 3 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAE | 1 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 0 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (STEAE) | 1 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-threatening TEAE | 1 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Non-STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAE | 10 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 4 TEAE | 1 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | STEAE leading to discontinuation of AMG 211 | 3 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAE | 8 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of AMG 211 | 3 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 1 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 10 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (STEAE) | 9 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE (STEAE) | 1 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 2 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Non-STEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE leading to discontinuation of AMG 211 | 0 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAE | 2 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Life-threatening TEAE | 0 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 4 TEAE | 0 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Fatal TEAE | 0 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAE | 2 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | STEAE leading to discontinuation of AMG 211 | 0 Participants |
Secondary
Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 28 Days
Area under the serum concentration-time curve (AUC) from time 0 to the last quantifiable concentration was estimated using the linear trapezoidal method.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 28-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 28 Days | 1040 day*ng/mL | Standard Deviation 245 |
| AMG 211 200 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 28 Days | 3250 day*ng/mL | Standard Deviation 1700 |
| AMG 211 400 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 28 Days | 2610 day*ng/mL | Standard Deviation 1940 |
| AMG 211 800 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 28 Days | 6080 day*ng/mL | Standard Deviation 99999 |
Secondary
Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Area under the serum concentration-time curve (AUC) from time 0 to the last quantifiable concentration was estimated using the linear trapezoidal method.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 7- or 14-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 29.7 day*ng/mL | Standard Deviation 19.4 |
| AMG 211 200 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 138 day*ng/mL | Standard Deviation 84.7 |
| AMG 211 400 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 172 day*ng/mL | Standard Deviation 23 |
| AMG 211 800 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 214 day*ng/mL | Standard Deviation 77.5 |
| AMG 211 1600 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 617 day*ng/mL | Standard Deviation 186 |
| AMG 211 1600 µg/Day for 28 Days | Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 1540 day*ng/mL | Standard Deviation 936 |
| AMG 211 3200 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 1420 day*ng/mL | Standard Deviation 666 |
Secondary
Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 28 Days
Area under the serum concentration-time curve from time 0 to infinity was estimated using the linear trapezoidal method
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 28-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 28 Days | 1040 day*ng/mL | Standard Deviation 245 |
| AMG 211 200 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 28 Days | 3260 day*ng/mL | Standard Deviation 1710 |
| AMG 211 400 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 28 Days | 3180 day*ng/mL | Standard Deviation 2070 |
| AMG 211 800 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 28 Days | 6530 day*ng/mL | Standard Deviation 99999 |
Secondary
Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Area under the serum concentration-time curve from time 0 to infinity was estimated using the linear trapezoidal method
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 7- or 14-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 30.0 day*ng/mL | Standard Deviation 19.3 |
| AMG 211 200 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 140 day*ng/mL | Standard Deviation 85.6 |
| AMG 211 400 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 173 day*ng/mL | Standard Deviation 23.4 |
| AMG 211 800 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 215 day*ng/mL | Standard Deviation 77.5 |
| AMG 211 1600 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 619 day*ng/mL | Standard Deviation 186 |
| AMG 211 1600 µg/Day for 28 Days | Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 1540 day*ng/mL | Standard Deviation 938 |
| AMG 211 3200 µg/Day for 14 Days | Area Under the Serum Concentration-Time Curve From Time 0 to Infinity (AUCinf) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 1430 day*ng/mL | Standard Deviation 673 |
Secondary
Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 28 Days
Css was calculated as the average concentration between achievement of plateau and the end of infusion.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 28-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 28 Days | 35.9 ng/mL | Standard Deviation 7.5 |
| AMG 211 200 µg/Day for 14 Days | Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 28 Days | 130 ng/mL | Standard Deviation 63.9 |
| AMG 211 400 µg/Day for 14 Days | Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 28 Days | 109 ng/mL | Standard Deviation 36.1 |
| AMG 211 800 µg/Day for 14 Days | Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 28 Days | 306 ng/mL | Standard Deviation 99999 |
Secondary
Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Css was calculated as the average concentration between achievement of plateau and the end of infusion.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion
Population: Participants who received 7- or 14-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 4.32 ng/mL | Standard Deviation 3.27 |
| AMG 211 200 µg/Day for 14 Days | Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 9.92 ng/mL | Standard Deviation 6.05 |
| AMG 211 400 µg/Day for 14 Days | Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 12.4 ng/mL | Standard Deviation 1.73 |
| AMG 211 800 µg/Day for 14 Days | Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 16.6 ng/mL | Standard Deviation 4.42 |
| AMG 211 1600 µg/Day for 14 Days | Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 45.3 ng/mL | Standard Deviation 12.9 |
| AMG 211 1600 µg/Day for 28 Days | Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 88.0 ng/mL | Standard Deviation 26.4 |
| AMG 211 3200 µg/Day for 14 Days | Concentration of AMG 211 at Steady State (Css) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 96.9 ng/mL | Standard Deviation 50.8 |
Secondary
Duration of Response
Duration of response was defined as the number of days between the date of the first tumor assessment indicating an objective response through to the subsequent date of progression as classified by modified irRC or death due to any cause. Analyzed in participants with an overall objective response. Overall objective response was defined as a best response of immune-related Complete Response (irCR) or immune-related Partial Response (irPR), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment. irCR: Complete disappearance of all lesions and no new lesions. irPR: Decrease in tumor burden ≥ 50% relative to baseline.
Time frame: Disease response was assessed every second cycle (8-10 weeks) until 4 weeks after the last dose. The median time frame was 75.5 days.
Population: No participant had an objective response.
Secondary
Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 28-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 45.4 ng/mL | Standard Deviation 8.86 |
| AMG 211 200 µg/Day for 14 Days | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 150 ng/mL | Standard Deviation 68.6 |
| AMG 211 400 µg/Day for 14 Days | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 145 ng/mL | Standard Deviation 45 |
| AMG 211 800 µg/Day for 14 Days | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 398 ng/mL | Standard Deviation 99999 |
Secondary
Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Levels of AMG 211 in plasma samples collected during this study were analyzed using an electrochemiluminiscence assay. The lower limit of quantification (LLOQ) of the assay was 0.10 ng/mL.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 7- or 14-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 5.32 ng/mL | Standard Deviation 2.26 |
| AMG 211 200 µg/Day for 14 Days | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 11.5 ng/mL | Standard Deviation 7.21 |
| AMG 211 400 µg/Day for 14 Days | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 13.9 ng/mL | Standard Deviation 1.13 |
| AMG 211 800 µg/Day for 14 Days | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 19.8 ng/mL | Standard Deviation 3.67 |
| AMG 211 1600 µg/Day for 14 Days | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 55.1 ng/mL | Standard Deviation 11 |
| AMG 211 1600 µg/Day for 28 Days | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 116 ng/mL | Standard Deviation 32.4 |
| AMG 211 3200 µg/Day for 14 Days | Maximum Observed Concentration (Cmax) of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 129 ng/mL | Standard Deviation 51 |
Secondary
Number of Participants With an Overall Objective Response
Disease response was assessed by radiological imaging using standardized contrast-enhanced magnetic imaging (MRI) or computed tomography (CT), and evaluated according to the modified Immune-Related Response Criteria (irRC). Overall objective response was defined as a best response of immune-related Complete Response (irCR) or immune-related Partial Response (irPR), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment. irCR: Complete disappearance of all lesions and no new lesions. irPR: Decrease in tumor burden ≥ 50% relative to baseline.
Time frame: Disease response was assessed every second cycle (8-10 weeks) until 4 weeks after the last dose. The median time frame was 75.5 days.
Population: Safety Analysis Set: all participants who enrolled and received at least one dose of AMG 211.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With an Overall Objective Response | 0 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With an Overall Objective Response | 0 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With an Overall Objective Response | 0 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With an Overall Objective Response | 0 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With an Overall Objective Response | 0 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With an Overall Objective Response | 0 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With an Overall Objective Response | 0 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With an Overall Objective Response | 0 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With an Overall Objective Response | 0 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With an Overall Objective Response | 0 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With an Overall Objective Response | 0 Participants |
Secondary
Number of Participants With Anti-AMG 211 Antibody Formation
Blood samples collected during the study were tested for anti-AMG 211 binding antibodies using an electrochemiluminescence-based bridging immunoassay. The number of participants with anti-AMG 211 antibody formation includes participants with a negative or no result at baseline and a positive antibody binding result postbaseline.
Time frame: Predose and 24 hours after the end of infusion during each treatment cycle, until 4 weeks after the last dose. Median time frame was 75.5 days.
Population: Safety Analysis Set: all participants who enrolled and received at least one dose of AMG 211. Participants with a negative or no result for anti-AMG 211 antibodies at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Number of Participants With Anti-AMG 211 Antibody Formation | 1 Participants |
| AMG 211 200 µg/Day for 14 Days | Number of Participants With Anti-AMG 211 Antibody Formation | 1 Participants |
| AMG 211 400 µg/Day for 14 Days | Number of Participants With Anti-AMG 211 Antibody Formation | 0 Participants |
| AMG 211 800 µg/Day for 14 Days | Number of Participants With Anti-AMG 211 Antibody Formation | 3 Participants |
| AMG 211 1600 µg/Day for 14 Days | Number of Participants With Anti-AMG 211 Antibody Formation | 1 Participants |
| AMG 211 1600 µg/Day for 28 Days | Number of Participants With Anti-AMG 211 Antibody Formation | 3 Participants |
| AMG 211 3200 µg/Day for 14 Days | Number of Participants With Anti-AMG 211 Antibody Formation | 5 Participants |
| AMG 211 3200 µg/Day for 28 Days | Number of Participants With Anti-AMG 211 Antibody Formation | 3 Participants |
| AMG 211 6400 µg/Day for 14 Days | Number of Participants With Anti-AMG 211 Antibody Formation | 3 Participants |
| AMG 211 6400 µg/Day for 28 Days | Number of Participants With Anti-AMG 211 Antibody Formation | 10 Participants |
| AMG 211 12,800 µg/Day for 28 Days | Number of Participants With Anti-AMG 211 Antibody Formation | 2 Participants |
Secondary
Progression Free Survival (PFS) at 6 Months in Participants Treated at the MTD
PFS was defined as the percentage of participants who were progression-free at 6 months. Immune-related progressed disease (irPD) was defined as an increase in tumor burden ≥ 25% relative to nadir (minimum recorded tumor burden), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment.
Time frame: 6 months
Population: Per protocol, only participants treated at the MTD for 6 months were to be included for this analysis. Because the MTD was not determined in this early-terminated study, this analysis could not be performed.
Secondary
Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days
Serum clearance (CL) calculated as CL = (actual dose)/(serum concentrations at steady-state \[Css\] x 24).
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 28-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 1.91 L/hr | Standard Deviation 0.412 |
| AMG 211 200 µg/Day for 14 Days | Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 1.17 L/hr | Standard Deviation 0.45 |
| AMG 211 400 µg/Day for 14 Days | Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 2.66 L/hr | Standard Deviation 0.752 |
| AMG 211 800 µg/Day for 14 Days | Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 1.75 L/hr | Standard Deviation 99999 |
Secondary
Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Serum clearance (CL) calculated as CL = (actual dose)/(serum concentrations at steady-state \[Css\] x 24).
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 7- or 14-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 2.93 L/hr | Standard Deviation 2.18 |
| AMG 211 200 µg/Day for 14 Days | Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 1.36 L/hr | Standard Deviation 1.28 |
| AMG 211 400 µg/Day for 14 Days | Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 1.36 L/hr | Standard Deviation 0.175 |
| AMG 211 800 µg/Day for 14 Days | Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 2.13 L/hr | Standard Deviation 0.609 |
| AMG 211 1600 µg/Day for 14 Days | Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 1.57 L/hr | Standard Deviation 0.519 |
| AMG 211 1600 µg/Day for 28 Days | Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 1.62 L/hr | Standard Deviation 0.446 |
| AMG 211 3200 µg/Day for 14 Days | Serum Clearance of AMG 211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 3.21 L/hr | Standard Deviation 1.31 |
Secondary
Terminal Half-life of AMG-211 in Cycle 1 in Participants Who Received Dosing for 28 Days
Terminal half-life (t1/2,z) calculated as t1/2,z = ln(2)/λz, where λz was the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 28-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Terminal Half-life of AMG-211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 11.1 hours | Standard Deviation 3.45 |
| AMG 211 200 µg/Day for 14 Days | Terminal Half-life of AMG-211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 6.48 hours | Standard Deviation 5.16 |
| AMG 211 400 µg/Day for 14 Days | Terminal Half-life of AMG-211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 8.81 hours | Standard Deviation 4.58 |
| AMG 211 800 µg/Day for 14 Days | Terminal Half-life of AMG-211 in Cycle 1 in Participants Who Received Dosing for 28 Days | 15.2 hours | Standard Deviation 99999 |
Secondary
Terminal Half-life (T1/2) of AMG-211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Terminal half-life (t1/2,z) calculated as t1/2,z = ln(2)/λz, where λz was the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 7- or 14-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Terminal Half-life (T1/2) of AMG-211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 10.4 hours | Standard Deviation 3.34 |
| AMG 211 200 µg/Day for 14 Days | Terminal Half-life (T1/2) of AMG-211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 10.3 hours | Standard Deviation 0.703 |
| AMG 211 400 µg/Day for 14 Days | Terminal Half-life (T1/2) of AMG-211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 10.2 hours | Standard Deviation 4.37 |
| AMG 211 800 µg/Day for 14 Days | Terminal Half-life (T1/2) of AMG-211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 7.25 hours | Standard Deviation 2.63 |
| AMG 211 1600 µg/Day for 14 Days | Terminal Half-life (T1/2) of AMG-211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 7.78 hours | Standard Deviation 2.37 |
| AMG 211 1600 µg/Day for 28 Days | Terminal Half-life (T1/2) of AMG-211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 10.3 hours | Standard Deviation 1.72 |
| AMG 211 3200 µg/Day for 14 Days | Terminal Half-life (T1/2) of AMG-211 in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 11.9 hours | Standard Deviation 3.53 |
Secondary
Time to Response
Time to response was defined as the number of days from the first administration of AMG 211 to the first objective assessment of response as per modified irRC. Analyzed in participants with an overall objective response. Overall objective response was defined as a best response of immune-related Complete Response (irCR) or immune-related Partial Response (irPR), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment. irCR: Complete disappearance of all lesions and no new lesions. irPR: Decrease in tumor burden ≥ 50% relative to baseline.
Time frame: Disease response was assessed every second cycle (8-10 weeks) until 4 weeks after the last dose. The median time frame was 75.5 days.
Population: No participant had an objective response.
Secondary
Time to Tumor Progression in Participants Treated at the Maximum Tolerated Dose (MTD)
Disease was assessed by radiological imaging using standardized contrast-enhanced MRI or CT, and evaluated according to the modified irRC. Immune-related progressed disease (irPD) was defined as an increase in tumor burden ≥ 25% relative to nadir (minimum recorded tumor burden), confirmed by a repeat, consecutive assessment no less than 4 weeks from the date of the first documented assessment.
Time frame: From first dose of AMG 211 until tumor progression, assessed through the end of study (up to 4 weeks after the last dose). The median time frame was 75.5 days.
Population: Per protocol, only participants treated at the MTD were to be included for this analysis. Because the MTD was not determined in this early-terminated study, this analysis could not be performed.
Secondary
Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 28 Days
Volume of distribution at steady-state calculated as (CL x t1/2,z)/0.693.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 hours after the start of infusion, Day 15, at the end of infusion (Day 29), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 28-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 28 Days | 31.3 liters | Standard Deviation 15 |
| AMG 211 200 µg/Day for 14 Days | Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 28 Days | 11.8 liters | Standard Deviation 12.4 |
| AMG 211 400 µg/Day for 14 Days | Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 28 Days | 33.4 liters | Standard Deviation 23.5 |
| AMG 211 800 µg/Day for 14 Days | Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 28 Days | 40.3 liters | Standard Deviation 99999 |
Secondary
Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days
Volume of distribution at steady-state calculated as (CL x t1/2,z)/0.693.
Time frame: Cycle 1: Predose, 2, 6, 24, 48-96, and 168 (for 14-day dosing groups only) hours after the start of infusion, at the end of infusion (Day 8 or Day 15), and 0.5, 2, 4, 8, and 24 hours after the end of infusion.
Population: Participants who received 7- or 14-day dosing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG 211 200 µg/Day for 7/14 Days | Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 50.8 liters | Standard Deviation 50.6 |
| AMG 211 200 µg/Day for 14 Days | Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 20.2 liters | Standard Deviation 18.8 |
| AMG 211 400 µg/Day for 14 Days | Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 19.2 liters | Standard Deviation 6.11 |
| AMG 211 800 µg/Day for 14 Days | Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 22.4 liters | Standard Deviation 10.8 |
| AMG 211 1600 µg/Day for 14 Days | Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 18.5 liters | Standard Deviation 11.4 |
| AMG 211 1600 µg/Day for 28 Days | Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 23.5 liters | Standard Deviation 5.12 |
| AMG 211 3200 µg/Day for 14 Days | Volume of Distribution at Steady-state (Vss) in Cycle 1 in Participants Who Received Dosing for 7 or 14 Days | 50.9 liters | Standard Deviation 13.5 |